Methods of making Efavirens and intermediates thereof

ABSTRACT

The present invention provides a process for the preparation of Efavirenz. A compound of Formula 1: 
                         
may be prepared by a process comprising cyclizing, in the presence of a first base, a compound of Formula 5 with a haloformate of Formula 6. Other processes are also provided as well as novel compounds prepared by and used in such processes.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 12/505,627, filed Jul. 20, 2009, now U.S. Pat. No. 8,080,655.

TECHNICAL FIELD

This invention relates to the field of chemical synthesis of organiccompounds and in particular to a synthesis of Efavirenz andintermediates thereof.

BACKGROUND

A common feature of retrovirus replication is reverse transcription ofthe RNA genome by a virally encoded reverse transcriptase to generateDNA copies of human immunodeficiency virus (HIV) sequences. Therefore,reverse transcriptase is a clinically relevant target for thechemotherapy of retroviral infections.

It is known that a number of benzoxazinone compounds are effective inthe treatment of HIV which is the retrovirus that causes progressivedestruction of the human immune system with the resultant onset of AIDS.Among them, the(S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneof Formula 1 (Efavirenz) is not only a highly potent reversetranscriptase inhibitor, but also efficacious against HIV reversetranscriptase resistance.

U.S. Pat. No. 5,519,021 discloses certain benzoxazinones that are usefulin the inhibition of HIV reverse transciptase (including its resistantvarieties), the prevention or treatment of infection by HIV and thetreatment of AIDS, either as compounds, pharmaceutically acceptablesalts, pharmaceutical composition ingredients, whether or not incombination with other antivirals, immunomodulators, antibiotics orvaccines. Methods of treating AIDS and methods of preventing or treatinginfection by HIV are also described.

In U.S. Pat. No. 5,633,405 an improved synthesis of a highly potent HIVreverse transcription inhibitor is disclosed, involving an acetylide anda trifluoromethyl ketone which produces a chiral product in the presenceof a chiral amino alcohol. See also Tetrahedron Lett. 1995, 36, 8937 andJ. Org. Chem. 1998, 63, 8536.

U.S. Pat. No. 5,922,864 discloses an efficient method for thepreparation of a compound of(−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, also known as DMP-266, a reverse transcriptaseinhibitor using a cyclization reaction of the amino alcohol intermediatewith an alkyl or aryl chloroformate and a base.

U.S. Pat. No. 5,925,789 provides novel methods for the asymmetricsynthesis of(S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneof Formula 1 which is useful as a human immunodeficiency virus (HIV)reverse transcriptase inhibitor.

U.S. Pat. No. 5,952,528 discloses a process for enhancing the purity of2R-[1-hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroanilinecomprising the formation of an acid addition salt which is capable ofrejecting the racemate in the selected organic solvent.

U.S. Pat. No. 6,015,926 discloses an efficient method for thepreparation of key intermediate, in the synthesis of(−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,a reverse transcriptase inhibitor is achieved using a chiral additionreaction to the 4-chloro-2-trifluoromethylketoaniline with an organozinccomplex to give the desired alcohol. This instant method has broadapplicability in the chiral addition to any prochiral ketone.

U.S. Pat. No. 7,205,402 provides novel methods for the synthesis of(S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneof Formula 1 which is useful as a human immunodeficiency virus (HIV)reverse transcriptase inhibitor.

U.S. Pat. No. 7,439,400 disclosed a new process of asymmetricalkynylation of ketone or ketimine, involving the chiral ligand-mediatedasymmetric addition of zinc or copper acetylide to a trifluoromethylketone or ketimine intermediate to give a chiral tertiary propargylicalcohols or amines. The adduct compounds include the key precursors tothe potent HIV reverse transcriptase inhibitor Efavirenz (DMP 266), DPC961 and DPC 083. The invention also disclosed a novel chiral aminoligand.

SUMMARY

The present invention is directed to methods of preparation ofEfavirenz, various intermediates useful in the preparation of Efavirenzand methods of preparation of such intermediates.

In some embodiments, the present invention allows for removal of theaniline auxiliary group of a compound of Formula 5 during thecyclization step without additional chemical reagent or treatment.

In some embodiments, the stereoselectivity of the cyclopropylacetylidereaction may be controlled by introduction of an appropriate chiralcarbonyl auxiliary group on the aniline nitrogen. The product of such anasymmetric addition may then undergo a cyclization reaction withconcomitant removal of the chiral auxiliary group, without the need fora discrete deprotection step.

In illustrative embodiments of the present invention there is provided aprocess for the preparation of a compound of Formula 1:

the process comprising cyclizing, in the presence of a first base, acompound of Formula 5:

with a haloformate of Formula 6:

wherein R¹ is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl or a chiral auxiliary group; R³ isalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted arylalkyl; and X is halogen.

In illustrative embodiments of the present invention there is provided aprocess described herein further comprising treatment with a secondbase.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein an intermediate of Formula 7:

is isolated before treatment with the second base, wherein R¹ is alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl or a chiral auxiliary group; and R³ is alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, or substituted arylalkyl.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the second base is selected from thegroup consisting of sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,triethylamine diisopropylethylamine, N,N-dimethylaniline, andN,N-diethylaniline, pyridine and mixtures thereof.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein R¹ is selected from the groupconsisting of methyl, ethyl, isobutyl, tert-butyl, and benzyl.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein R¹ is a chiral auxiliary group.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the compound of Formula 5 is(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the compound of Formula 5 is(R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylamino)-2-oxo-1-phenylethylpivalate.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the haloformate of Formula 6 isselected from the group consisting of 4-nitrophenyl haloformate,4-chlorophenyl haloformate, phenyl haloformate and 1-chloroethylhaloformate.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the first base is selected from thegroup consisting of sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,triethylamine diisopropylethylamine, N,N-dimethylaniline, andN,N-diethylaniline, pyridine and mixtures thereof.

In illustrative embodiments of the present invention there is provided aprocess for making a compound of Formula 5:

the process comprising: i) reacting a compound of Formula 2:

or an acid addition salt thereof, with a chiral acylating agent ofFormula R²COG to form a compound of Formula 3, Formula 3a or a mixturethereof:

ii) reacting the compound of Formula 3, Formula 3a or the mixturethereof with a compound of Formula 4:

to form the compound of Formula 5, wherein R² is a chiral auxiliarygroup; G is a hydroxyl group, or a leaving group; and M is a metal.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein G is chloro or the hydroxyl group andR² is:

In illustrative embodiments of the present invention there is provided aprocess described herein wherein G is chloro and R² is:

In illustrative embodiments of the present invention there is provided aprocess described herein wherein R² is:

R⁴ is a hydroxyl protecting group; and the carbon center designated “*”is enantiomerically enriched in a (R)- or (S)-configuration.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein M is lithium, sodium, potassium,magnesium halide or mixtures thereof.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein M is lithium.

In illustrative embodiments of the present invention there is provided aprocess for the preparation of a compound of Formula 1:

the process comprising: i) reacting a compound of Formula 2:

or an acid addition salt thereof, with a chiral acylating agent ofFormula R²COG to form a compound of Formula 3, Formula 3a or a mixturethereof:

ii) reacting the compound of Formula 3, Formula 3a or the mixturethereof with a compound of Formula 4:

to form a compound of Formula 5:

iii) hydrolysing the compound of Formula 5 to form a compound of Formula8:

and iv) cyclizing the compound of Formula 8 to give the compound ofFormula 1, wherein R¹ and R² are a chiral auxiliary group; G is ahydroxyl group, or a leaving group; and M is a metal.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein G is chloro or the hydroxyl group andR¹ and R² are:

In illustrative embodiments of the present invention there is provided aprocess described herein wherein G is chloro and R¹ and R² are:

In illustrative embodiments of the present invention there is provided aprocess described herein wherein R¹ and R² are:

R⁴ is a hydroxyl protecting group; and the carbon centre designated “*”is enantiomerically enriched in a (R)- or (S)-configuration.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein M is lithium, sodium, potassium,magnesium halide or a mixture thereof.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein M is lithium.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the cyclization of a compound ofFormula 8 to give the compound of Formula 1 is performed with acyclization reagent selected from the group consisting of C₁-C₁₀ alkylhaloformates, C₆-C₁₂ aryl haloformates, phosgene, triphosgene and1,1′-carbonyldiimidazole.

In illustrative embodiments of the present invention there is provided acompound of Formula 3:

wherein R² is a chiral auxiliary group.

In illustrative embodiments of the present invention there is provided acompound of Formula 3a:

wherein R² is a chiral auxiliary group.

In illustrative embodiments of the present invention there is provided acompound of Formula 5:

wherein R¹ is a chiral auxiliary group.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the chiral auxilliary group is Q of achiral acid QCOOH, wherein QCOOH is selected from the group consistingof: natural chiral organic acids, natural chiral organic acidderivatives, unnatural chiral organic acids, unnatural chiral organicacid derivatives, natural amino acid derivatives, and unnatural aminoacid derivatives.

In illustrative embodiments of the present invention there is provided aprocess described herein wherein the chiral auxiliary group is a chiralC₁-C₁₀ alkoxyl or a chiral C₆-C₁₂ aralkoxyl group.

In illustrative embodiments of the present invention there is provided acompound of Formula 9:

In illustrative embodiments of the present invention there is provided acompound of Formula 10:

In illustrative embodiments of the present invention there is provided acompound of Formula 11:

In illustrative embodiments of the present invention there is provided acompound of Formula 12:

In illustrative embodiments of the present invention there is provided acompound of Formula 13:

In illustrative embodiments of the present invention there is provided acompound of Formula 14:

wherein R⁴ is a hydroxyl protecting group; and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.

In illustrative embodiments of the present invention there is provided acompound of Formula 15:

wherein R⁴ is a hydroxyl protecting group; and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.

In illustrative embodiments of the present invention there is provided acompound of Formula 7:

wherein R¹ is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl or a chiral auxiliary group; and R³ isalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted arylalkyl.

In illustrative embodiments of the present invention there is provided acomposition comprising a compound of Formula 1:

and a compound of Formula 7:

In illustrative embodiments of the present invention there is provided acomposition comprising a compound of Formula 1:

and a compound of Formula 5:

Other aspects and features of the present invention will become apparentto those ordinarily skilled in the art upon review of the followingdescription of specific embodiments of the invention in conjunction withthe accompanying figures.

DETAILED DESCRIPTION

As used herein, the term “substituted” refers to the replacement of ahydrogen atom on a compound with a substituent group. A substituent maybe a non-hydrogen atom or multiple atoms of which at least one is anon-hydrogen atom and one or more may or may not be hydrogen atoms. Forexample, without limitation, substituted compounds may comprise one ormore substituents selected from the group consisting of: R″, OR″,NR″R′″, SR″, halogen, SiR″R′″R″″, OC(O)R″, C(O)R″, CO₂R″, CONR″R′″,NR′″C(O)₂R″, S(O)R″, S(O)₂R″, CN and NO₂.

As used herein, each R″, R′″, and R″″ may be selected, independently,from the group consisting of: hydrogen, halogen, oxygen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, andarylalkyl groups.

As used herein, the term “alkyl” by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain, or cyclic hydrocarbon radical, or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated (e.g.C₁-C₁₀ or 1- to 10-membered means one to ten carbons). Examples ofsaturated hydrocarbon radicals include, but are not limited to, groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. An unsaturated alkyl group is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups include, butare not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers.

As used herein, the term “aryl” by itself or as part of anothersubstituent, means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (often from 1 to 3 rings) which are fused together or linkedcovalently. “Aryl” includes, but is not limited to, “heteroaryl” groups.“Heteroaryl” refers to an aryl group that contain from one to fourheteroatoms selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl andheteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. The term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl, etc.) including those alkylgroups in which a carbon atom containing group (e.g., a methylene group)has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc).

As used herein the term “leaving group” refers to a halogen atom (e.g.chlorine, bromine and iodine) and/or sulfonyloxy groups (e.g.methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy).

As used herein, the term “chiral auxiliary group” refers to any chiralchemical compound or unit that is temporarily incorporated into anorganic synthesis for the purpose of altering the stereochemical outcomeof a subsequent reaction. Chiral auxiliaries are optically activecompounds and introduce chirality in otherwise racemic compounds. Afterit has served its purpose the chiral auxiliary can be removed in a laterstep and recycled.

As used herein, “hydroxyl protecting group” refers to a protecting groupthat is introduced into a molecule by chemical modification of a hydroxygroup in order to obtain chemoselectivity in a subsequent chemicalreaction. Such hydroxyl protecting groups include those listed inGreene, T. W. and Wuts, P. G. M., “Chapter 2, Protection for thehydroxyl group, including 1,2- and 1,3-diols”, in “Protective Groups inOrganic Synthesis”, Fourth Edition, John Wiley & Sons, Inc., 2007, pp.16-366. Hydroxyl protecting group includes, but is not limited to 1)ethers, including silyl ethers such as trimethylsilyl (TMS) ether,tert-butyldimethylsilyl (TBDMS) ether, and triisopropylsilyl (TIPS)ether, tetrahydropyran (THP), β-methoxyethoxymethyl ether (MEM),p-methoxybenzyl ether (PMB), methoxymethyl ether (MOM), ethoxyethylethers (EE), methyl ether, benzyl ether, methylthiomethyl ether; and 2)esters such as pivaloyl (Piv) esters.

According to illustrative embodiments of the present invention, there isprovided a process for the preparation of a compound of Formula 1:

comprising cyclization, in the presence of a first base, of a compoundof Formula 5:

with a haloformate of Formula 6:

wherein

R¹ is C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₂ aryl, substitutedC₆-C₁₂ aryl, C₆-C₁₂ arylalkyl, substituted C₆-C₁₂ arylalkyl or a chiralauxiliary group;

R³ is C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₂ aryl, substitutedC₆-C₁₂ aryl, C₆-C₁₂ arylalkyl, or substituted C₆-C₁₂ arylalkyl; and

X is halogen;

optionally followed by treatment with a second base.

In some embodiments of Formula 5, R¹ is selected from the groupconsisting of C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₂ aryl,substituted C₆-C₁₂ aryl, C₆-C₁₂ arylalkyl and substituted C₆-C₁₂arylalkyl. In some embodiments of Formula 5, R¹ is selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, cyclopentyl, cyclohexyl, hexyl, phenyl, and benzyl. In someembodiments of Formula 5, R¹ is selected from the group consisting ofmethyl, ethyl, isobutyl, tert-butyl, and benzyl. In some embodiments ofFormula 5, R¹ is a chiral auxiliary group. In some embodiments ofFormula 5 the chiral auxiliary group is Q of a chiral acid QCOOH,wherein QCOOH is selected from natural chiral organic acids, naturalchiral organic acid derivatives, unnatural chiral organic acids,unnatural chiral organic acid derivatives, natural amino acidderivatives, and unnatural amino acid derivatives. In some embodimentsof Formula 5, R¹ is Q of a chiral acid QCOOH, wherein QCOOH is a chiralacid selected from the group consisting of camphanic acid,2-pyrrolidone-5-carboxylic acid, naproxen, ibuprofen; tartaric acid,malic acid, lactic acid, 3-hydroxybutyric acid, mandelic acid orderivatives thereof. In other embodiments of Formula 5, the chiralauxiliary group is a chiral alkoxyl or chiral aralkoxyl group such asthe menthoxy or camphanoxy groups:

In some embodiments of Formula 5 the chiral auxiliary group is one ofthe following two groups:

wherein R⁴ is a hydroxyl protecting group, and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.

In some embodiments, the haloformate of Formula 6 is selected from thegroup consisting of C₁-C₁₀ alkyl haloformate, substituted C₁-C₁₀ alkylhaloformate, C₆-C₁₂ aryl haloformate, and substituted C₆-C₁₂ arylhaloformate. In some embodiments, the haloformate of Formula 6 isselected from the group consisting of methyl haloformate, ethylhaloformate, hydroxymethyl haloformate, hydroxyethyl haloformate,1-chloroethyl haloformate, 2-chloroethyl haloformate, phenylhaloformate, hydroxyphenyl haloformate, dihydroxyphenyl haloformate,trihydroxyphenyl haloformate, methyoxyphenyl haloformate, chlorophenylhaloformate, dichlorophenyl haloformate, trichlorophenyl haloformate,pentachlorophenyl haloformate and 4-nitrophenyl haloformate. In someembodiments, the haloformate of Formula 6 is selected from the groupconsisting of 4-nitrophenyl haloformate, phenyl haloformate and1-chloroethyl haloformate.

The first and second base may be the same or different. The first and/orsecond base may be any of a variety of bases which facilitates thedesired reaction. The first and/or second base may be an organic orinorganic base. The first and/or second base may be selected from thegroup consisting of sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine and mixtures thereof. The first and/orsecond base may be triethylamine, diisopropylamine, sodium hydroxide orpotassium carbonate.

In some embodiments, the cyclization is a step-wise process, whereby thecompound of Formula 5 is treated with the haloformate of Formula 6 inthe presence of the first base to form an intermediate carbonate ofFormula 7:

wherein R¹ may be as defined above for Formula 5 and R³ may be asdefined above for Formula 6. The intermediate carbonate of Formula 7 issubsequently treated with the second base to induce cyclization. Theintermediate carbonate of Formula 7 may or may not be isolated beforetreatment with the second base. The isolation of the carbonate ofFormula 7 also provides for an additional opportunity to purify and insome cases may provide for a purer product. In a step-wise process, thesame solvent may be used throughout or a different solvent may be usedfor each step.

Since the same solvent may be used throughout, in some embodiments, thecyclization may also be carried out in a one-step and/or a one-potprocess, whereby cyclization of the compound of Formula 5 occurs upontreatment with the haloformate in the presence of the first base. Insome embodiments, the first base may be added in a portion wise process.

The cyclization may occur in a first solvent. The first solvent may beselected from group consisting of C₁-C₁₀ alkyl ethers (e.g. diethylether, methyl t-butyl ether, diisopropyl ether, butyl ether), C₁-C₁₀alkyl esters (e.g. ethyl acetate), C₁-C₁₀ ketones (e.g. acetone, methylethyl ketone, methyl isobutyl ketone), C₆-C₁₂ aromatic hydrocarbons andC₁-C₁₀ aliphatic hydrocarbons (e.g. toluene, xylenes, hexanes andheptanes), C₁-C₁₂ nitriles, (e.g. acetonitile, propionitrile,butyronitrile, and benzonitrile) C₁-C₁₂ N,N-dialkylamides (e.g.N,N-dimethylformamide, N,N-dimethylacetamide andN-methyl-2-pyrrolidinone), C₁-C₁₀ sulfoxides and C₁-C₁₀ sulfones (e.g.dimethyl sulfoxide and sulfolane), halogenated C₁-C₁₀ hydrocarbons (e.g.dichloromethane and dichloroethane), water and mixtures thereof. Thefirst solvent may be toluene, dichloromethane, methyl t-butyl ether orN,N-dimethylformamide.

The compound of Formula 5, may be prepared by acylation of a compound ofFormula 8:

according to known methods in the art, for example, see Francis A. Careyand Richard J. Sundberg, “Advanced Organic Chemistry, Part B: Reactionsand Synthesis”, Fifth Edition, Springer, 2007, pages 252-258. Thecompound of Formula 8 may be prepared according to the method describedin this invention or other methods known in the art.

According to illustrative embodiments of the present invention there isprovided a process for the preparation of a compound of Formula 5wherein R¹ is a chiral auxiliary group, the process comprising:

i) reacting a compound of Formula 2:

or an acid addition salt thereof, with a chiral acylating agent ofFormula R²COG to form a compound of Formula 3, 3a or mixtures thereof:

and

ii) reacting the compound of Formula 3, 3a or mixtures thereof with acompound of Formula 4:

to give a compound of Formula 5,wherein

R² is a chiral auxiliary group;

G is a hydroxyl group, or a leaving group; and

M is a metal.

In some embodiments of Formula 3 and/or 3a, R² is Q of a chiral acidQCOOH, wherein QCOOH is selected from natural chiral organic acids,natural chiral organic acid derivatives, unnatural chiral organic acids,unnatural chiral organic acid derivatives, natural amino acidderivatives, and unnatural amino acid derivatives. In other embodimentsof Formula 3 and/or 3a, the chiral auxiliary group is a chiral alkoxylor chiral aralkoxyl group such as the menthoxy or camphanoxy group. Insome embodiments of Formula 3 and/or 3a, R² is Q of a chiral acid QCOOH,wherein QCOOH is a chiral acid selected from the group consisting ofcamphanic acid, 2-pyrrolidone-5-carboxylic acid, naproxen, ibuprofen;tartaric acid, malic acid, lactic acid, 3-hydroxybutyric acid, mandelicacid and derivatives thereof. In some embodiments of Formula 3 and/or3a, R² is one of the following two groups:

wherein R⁴ is a hydroxyl protecting group, and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.

The leaving group G may be independently selected from the groupconsisting of: halogen atoms (e.g. chlorine, bromine and iodine) andsulfonyloxy groups (e.g. methanesulfonyloxy,trifluoromethanesulfonyloxy, p-toluenesulfonyloxy). In some embodiments,G is chlorine.

The chiral acylating agent of Formula R²COG may be (−)-camphanic acid,(−)-camphanoyl chloride, or (R)-2-chloro-2-oxo-1-phenethyl pivalate.

The reaction of the compound of Formula 2 and the chiral acylating agentmay occur in the presence of a third base in a second solvent. The thirdbase may be any of a variety of bases which facilitates the desiredreaction. The third base may be organic or inorganic. The third base maybe selected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, potassium carbonate,lithium carbonate, triethylamine, diisopropylethylamine,N,N-dimethlyaniline, N,N-diethylaniline, pyridine, and mixtures thereof.

In some embodiments, when G is a hydroxyl group, the reaction of thecompound of Formula 2 and the chiral acylating agent may occur in thepresence of an acid catalyst in the second solvent. The acid catalystmay be organic or inorganic. The acid catalyst may be selected from thegroup consisting of sulfuric acid, hydrogen chloride, p-toluenesulfonicacid, benzenesulfonic acid, and mixtures thereof.

The second solvent may be selected from the group consisting of C₁-C₁₀alkyl ethers (e.g. diethyl ether, methyl t-butyl ether, diisopropylether, butyl ether), C₁-C₁₀ alkyl esters (e.g. ethyl acetate), C₁-C₁₀ketones (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone),aromatic C₆-C₁₂ hydrocarbons and aliphatic C₁-C₁₀ hydrocarbons (e.g.toluene, xylenes, hexanes and heptanes), C₁-C₁₀ nitriles, (e.g.acetonitile, propionitrile, butyronitrile, and benzonitrile) C₁-C₁₂N,N-dialkylamides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide andN-methyl-2-pyrrolidinone), C₁-C₁₀ sulfoxides and C₁-C₁₀ sulfones (e.g.dimethyl sulfoxide and sulfolane), halogenated C₁-C₁₀ hydrocarbons (e.g.dichloromethane and dichloroethane), water and mixtures thereof. Thesecond solvent may be dichloromethane.

The metal may be a salt of a divalent cation, such as Zn²⁺ or Mg²⁺, or amonovalent cation, such as Li⁺, Na⁺ or K⁺. The cyclopropyl acetylidemetal reagent may be prepared in situ from the reaction of cyclopropylacetylene and an organometallic compound. The organometallic compoundmay be selected from the group consisting of organomagnesium,organozinc, organosodium, organolithium compounds and mixtures thereof.The organometallic compound may be selected from the group consisting ofalkylmagnesium halide, alkylzinc halide, alkyllithium, lithiumhexaalkyldisilazide, sodium hexaalkyldisilazide, and potassiumhexaalkyldisilazide. The organometallic compound may be selected fromthe group consisting of ethylmagnesium chloride, methylmagnesiumchloride, n-butyllithium, sec-butyllithium, tert-butyllithium,n-hexyllithium and lithium hexamelthyldisilazide.

The reaction of a compound of Formula 3 and/or 3a with a compound ofFormula 4 may be done in the presence of a third solvent. The thirdsolvent may be an aprotic solvent. The third solvent may be an C₁-C₁₀alkyl ether. The third solvent may be tetrahydrofuran.

The reaction may be done at a temperature range between about −78° C. toabout 30° C.,

In some embodiments, reaction of a compound of Formula 3 and/or 3a witha compound of Formula 4 may give a mixture of two diastereomers of theFormula 5 and 5a:

wherein a desired isomer of the compound of Formula 5 is a major productand R¹ is a chiral auxiliary group. The ratio between the 5 (S) and 5a(R) isomers may range from about 1.1:1 to >99:1. The desired isomer canthen be isolated using typical separation methods including selectivecrystallization.

According to illustrative embodiments of the present invention there isprovided a process for the preparation of the compound of Formula 1:

the process comprising:

i) reacting a compound of Formula 2:

or an acid addition salt thereof, with a chiral acylating agent ofFormula R²COG to form a compound of Formula 3, 3a or mixtures thereof:

ii) reacting the compound of Formula 3, 3a or mixtures thereof with acompound of Formula 4:

to give a compound of Formula 5:

iii) hydrolysing the compound of Formula 5 to form a compound of Formula8:

and;

iv) cyclizing the compound of Formula 8 to give the compound of Formula1,

wherein

R¹ is a chiral auxiliary group;

R² is a chiral auxiliary group;

G is a hydroxyl group, or a leaving group; and

M is a metal.

In some embodiments of Formula 3 and/or 3a, R² is Q of a chiral acidQCOOH, wherein QCOOH is selected from natural chiral organic acids,natural chiral organic acid derivatives, unnatural chiral organic acids,unnatural chiral organic acid derivatives, natural amino acidderivatives, and unnatural amino acid derivatives. In some embodimentsof Formula 3 and/or 3a, R² is Q of a chiral acid QCOOH, wherein QCOOH isa chiral acid selected from the group consisting of camphanic acid,2-pyrrolidone-5-carboxylic acid, naproxen, ibuprofen; tartaric acid,malic acid, lactic acid, 3-hydroxybutyric acid, mandelic acid orderivatives thereof. In other embodiments of Formula 3, the chiralauxiliary group is a chiral alkoxyl and chiral aralkoxyl groups such asthe menthoxy, and camphanoxy groups. In some embodiments of Formula 3and/or 3a, R² is one of the following two groups:

wherein R⁴ is a hydroxyl protecting group, and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.

R¹ of the compound of Formula 5 is necessarily related to the R² groupof the precursor compound of Formulas 3, 3a or mixtures thereof.Generally, R¹ and R² will be the same for any given reaction of thissort. Hence, R¹ is as defined for R² in reactions where the compound ofFormula 5 is generated from the compound of Formula 3, 3a or mixturesthereof.

The leaving group G may be independently selected from the groupconsisting of: halogen atoms (e.g. chlorine, bromine and iodine) andsulfonyloxy groups (e.g. methanesulfonyloxy,trifluoromethanesulfonyloxy, p-toluenesulfonyloxy). In some embodiments,G is chlorine.

The chiral acylating agent of Formula R²COG may be (−)-camphanic acid,(−)-camphanoyl chloride or (R)-2-chloro-2-oxo-1-phenethyl pivalate.

The reaction of a compound of Formula 2 and a chiral acylating agent mayoccur in the presence of a third base or an acid catalyst and typicallyin the second solvent as described above.

The metal may be a salt of a divalent cation, such as Zn²⁺ or Mg²⁺, or amonovalent cation, such as Li⁺, Na⁺ or K⁺. The cyclopropyl acetylidemetal reagent may be prepared in situ from the reaction of cyclopropylacetylene and an organometallic compound. The organometallic compoundmay be selected from the group consisting of organomagnesium,organozinc, organosodium, organolithium compounds and mixtures thereof.The organometallic compound may be selected from the group consisting ofalkylmagnesium halide, alkylzinc halide, alkyllithium, lithiumhexaalkyldisilazide, sodium hexaalkyldisilazide, and potassiumhexaalkyldisilazide. The organometallic compound may be selected fromthe group consisting of ethylmagnesium chloride, methylmagnesiumchloride, n-butyllithium, sec-butyllithium, tert-butyllithium,n-hexyllithium and lithium hexamelthyldisilazide.

The reaction of the compound of Formula 3 and/or 3a with the compound ofFormula 4 may be done in the presence of a third solvent. The thirdsolvent may be an aprotic solvent. The third solvent may be an alkylether. The third solvent may be tetrahydrofuran.

The reaction may be done at a temperature range between about −78° C. toabout 30° C.

Hydrolysis of the compound of Formula 5 to the compound of Formula 8 maybe performed under acidic or basic conditions.

The cyclization of the compound of Formula 8 to give the compound ofFormula 1 may be performed with a cyclization reagent. The cyclizationreagent may be selected from the group consisting of alkyl haloformates,aryl haloformates, phosgene, triphosgene and 1,1′-carbonyldiimidazole.

EXAMPLES

The following examples are illustrative of some of the embodiments ofthe invention described herein. These examples should not be consideredto limit the spirit or scope of the invention in any way.

Example 1 Preparation of1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2)

A solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanonehydrochloride hydrate (48.5 g, 174.4 mmol), 300 mL toluene, and 150 mLwater was stirred at room temperature for 30 minutes. The pH of thesolution was adjusted to 7-8 via the addition of saturated aqueousNaHCO₃ solution. The resulting mixture was then separated, and thetoluene layer was collected and evaporated to dryness to give 38.2 g1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2) as a yellowsolid.

Example 2 Preparation of(1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9)

A solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0g, 22.4 mmol), (−)-camphanoyl chloride (7.35 g, 33.9 mmol), and 50 mLdichloromethane was stirred at room temperature. Triethylamine (1.0 mL,7.19 mmol, 0.3 eq) was added dropwise. The reaction mixture was stirredovernight at room temperature. The resulting suspension was treated with10% critic acid aqueous, washed with water and brine. The organic layerwas separated and evaporated to dryness to give 8.05 g(1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9). ¹H NMR (CDCl₃) δ 11.48 (s,1H), 8.81 (d, J=9.1 Hz, 1H), 7.94 (s, 1H), 7.68 (ad, J=9.1 Hz, 1H),2.64-2.54 (m, 1H), 2.09-1.96 (m, 2H), 1.82-1.73 (m, 1H), 1.17 (s, 3H),1.15 (s, 3H), 0.99 (s, 3H).

Example 3 Preparation of (R)-2-chloro-2-oxo-1-phenylethyl pivalate

(R)-Mandelic acid (10 g, 65.7 mmol) was dissolved in toluene (20 mL) atwhich point pivaloyl chloride (10.2 mL, 82.9 mmol) was added. Thismixture was stirred at 60° C. for 3 hours. After cooling the reactionmixture to 30° C., toluene (10 mL), N,N-dimethylformamide (0.3 mL) andthionyl chloride (10 mL) were added. The reaction mixture was stirred at35° C. for 2 hours and then at 50° C. for 4 hours. Then the mixture wasevaporated to dryness to furnish 14.5 g (R)-2-chloro-2-oxo-1-phenylethylpivalate as a yellow oil.

Example 4 Preparation of(R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethylpivalate (12)

1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0 g, 22.4 mmol)was dissolved in dichloromethane (50 mL) and(R)-2-chloro-2-oxo-1-phenylethyl pivalate (8.54 g, 33.5 mmol) was added.To this mixture N,N-dimethylaniline (2.8 mL, 22.4 mmol) was added. Thereaction mixture was stirred at room temperature for 3 hours. Themixture was diluted with dichloromethane (50 mL), treated with 1N HCl,washed with brine and the organic layer was separated and evaporated togive(R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethylpivalate (12) as an brown oil.

Example 5 Preparation of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10)

Ethylmagnesium bromide 3M in ether (5.98 mL, 17.95 mmol) was addedslowly to a solution of cyclopropyl acetylene (1.19 g, 17.95 mmol) intetrahydrofuran (18 mL) in an ice-bath under argon and the mixture wasstirred at 40° C. for 3 hours. Then(1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(9, 1.45 g, 3.59 mmol) was added in portions while the flask was in anice-bath. The reaction mixture was stirred at room temperature for 2hours. The reaction was quenched with saturated aqueous NH₄Cl, and themixture was extracted with ethyl acetate and two layers were separated.The organic layer was evaporated to dryness to give 1.67 g of thecompound as a crude oil. It was further crystallized with petroleumether and ethyl acetate to furnish(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10) as a white or off-white solid. This solid was shown to be 98.8% deby HPLC.

¹H NMR (CDCl₃) δ 10.52 (s, 1H), 8.42 (d, J=8.9 Hz, 1H), 7.72 (s, 1H),7.35 (ad, J=8.9 Hz, 1H), 5.05 (s, 1H), 2.68-2.56 (m, 1H), 2.03-1.93 (m,2H), 1.74-1.65 (m, 1H), 1.44-1.35 (m, 1H), 1.14 (s, 3H), 1.13 (s, 3H),0.95 (s, 3H), 0.90-0.87 (m, 2H), 0.80-0.77 (m, 2H).

Example 6 Preparation of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10)

2.5 M n-Butyllithium (14.8 mL, 37.16 mmol) was added slowly to asolution of cyclopropyl acetylene (2.46 g, 37.16 mmol) intetrahydrofuran (20 mL) in an ice-salt-bath under argon, and then(1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(9,5 g, 12.39 mmol) was added. The reaction mixture was stirred for 0.5hour. The reaction was quenched with 10% citric acid aqueous, themixture was extracted with ethyl acetate and the two layers wereseparated. The organic layer was evaporated to dryness to give crude oilwhich was further crystallized with ethyl acetate and petroleum ether togive(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10) as a white or off-white powder. ¹H NMR spectrum of the product wasidentical to that of Example 5.

Example 7 Preparation of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10)

1M LiHMDS (7.4 mL, 7.4 mmol) was added slowly to a solution ofcyclopropyl acetylene (0.49 g, 7.4 mmol) in THF (4 mL) in an ice-saltbath under argon, and then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(9, 1 g., 2.48 mmol) in THF (1.5 mL) was added slowly. The mixture wasstirred at −15° C. for 20 minutes. TLC showed the formation of theproduct. The reaction mixture was worked up similarly to the example 6,and(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10) was isolated as an off-white solid. ¹H NMR spectrum of the productwas identical to that of Example 5.

Example 8 Preparation of(R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylamino)-2-oxo-1-phenylethylpivalate (13)

Ethylmagnesium bromide 3 M in ether (2 mL, 6.2 mmol) was added slowly toa solution of cyclopropyl acetylene (0.41 g, 6.2 mmol) in THF (5 mL) inan ice-bath under argon. The mixture was stirred at 0° C. for 1 hour andthen 40° C. for 2 hours. Then(R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)phenylamino)-2-oxo-1-phenylethylpivalate (12, 0.55 g, 1.24 mmol) in THF (2 mL) was added slowly in anice-bath. The mixture was stirred at 0° C. for 1.5 hours. 10% Citricacid was added to quench the reaction. The organic layer was washed withwater and then evaporated to dryness to give(R)-2-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenylamino)-2-oxo-1-phenylethylpivalate (13). This solid was shown to be 35.9% de by chiral HPLC. Thepure product was isolated by chromatography.

Example 9 Preparation of6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one(racemic Efavirenz)

A solution ofN-(4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)acetamide(5, R¹ is methyl, 1.1 g, 3.3 mmol), toluene (5.5 mL) and triethylamine(0.5 mL, 3.65 mmol) was stirred at 0-5° C. under nitrogen then1-chloroethyl chloroformate (0.52 g, 3.65 mmol) was added dropwise. Themixture was stirred at 5-10° C. overnight. Water (20 mL) was added andthe mixture was separated. The organic layer was evaporated to drynesswhereupon N,N-dimethyl formamide (5 mL) and K₂CO₃ (0.9 g, 6.6 mmol) wereadded. The reaction mixture was stirred at room temperature for 1 day.Toluene (20 mL) and water (20 mL) were added to the mixture, and theresulting mixture was separated. The organic layer was washed with water(20 mL), and evaporated to dryness to give6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-oneas an off-white solid. ¹H NMR (CDCl₃) δ 9.64 (s, 1H), 7.49 (a, s, 1H),7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H),0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H),

Example 10 Preparation of (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one(Efavirenz, 1

A solution of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10, 5.0 g, 10.6 mmol), methyl tert-butyl ether (30 mL), 1 N NaOHaqueous (25 mL), and 4-nitrophenyl chloroformate (2.8 g, 13.8 mmol) wasstirred at room temperature for 10 minutes. Then two layers wereseparated and NaOH (2.1 g, 52.5 mmol) was added to the organic layer.The mixture was stirred for 1 hour. The suspension was filtered andrinsed with methyl tert-butyl ether (3×10 mL), then the filtrate waswashed with 1 N NaOH (25 mL), water (25 mL), and the two layers wereseparated. The organic layer was evaporated to about 10 mL, heptanes (25mL) was added. Then the mixture was stirred at room temperature for anhour, the resulting suspension was filtered and washed with heptanes togive 1.5 g(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one(Efavirenz, 1) as a white or off-white solid.

Example 11 Preparation of (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl1-chloroethyl carbonate (7, R¹ is4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R³ is 1-chloroethyl)

A solution of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10, 20 g, 42.6 mmol), dichloromethane (100 mL) and triethylamine (5.17g, 51.1 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethylchloroformate (7.3 g, 51.1 mmol) was added dropwise. The mixture wasstirred at 5-10° C. for 1 hour. Water (60 ml) was added with stirringand then the layers were separated. The organic solution wasconcentrated and MTBE (180 ml) was added. After washing with watertwice, the system was concentrated to 30 ml and then MTBE (10 ml) andhexane (60 ml) were added. The suspension was stirred at 70° C. for 30min and filtered to give(S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl1-chloroethyl carbonate (7, R¹ is4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R³ is 1-chloroethyl) asa white solid. ¹H NMR (CDCl₃) δ9.43, 9.30 (s, 1H), 8.17, 8.06 (d, J=8.7Hz, 1H), 7.62, 7.54 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.36 (q, J=5.7 Hz,1H), 2.60-2.50 (m, 1H), 2.09-1.93 (m, 2H), 1.89-1.86 (at, J=4.5 Hz, 3H),1.77-1.61 (m, 2H), 1.16 (d, J=10.5 Hz, 6H), 1.01 (d, J=7.5 Hz, 3H),0.97-0.92 (m, 2H), 0.88-0.84 (m, 2H).

Example 12 Preparation of(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one(Efavirenz, 1)

K₂CO₃ (13.3 g, 95.8 mmol) powder was added to a solution of(S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethylcarbonate (7, R¹ is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R³is 1-chloroethyl, 36.8 g, 63.9 mmol) in N,N-dimethylformamide (150 mL).The reaction mixture was stirred at room temperature overnight. Methylt-butyl ether (300 mL) and water (300 mL) were added to the mixture, andthe resulting layers were separated. The organic layer was washed withbrine and evaporated to 60 mL then petroleum ether (200 mL) was added.The resulting mixture was filtered and rinsed with petroleum ether togive(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one(Efavirenz, 1) as an off-white solid.

Example 13 Preparation of (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one(Efavirenz, 1)

A solution of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10, 30 g, 63.9 mmol), dichloromethane (150 mL) and triethylamine (7.11g, 70.2 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethylchloroformate (10.0 g, 70.2 mmol) was added dropwise. The mixture wasstirred at 5-10° C. for 1 hour. Then N,N-dimethylformamide (150 mL) wasadded and further evaporated to 220 mL, then K₂CO₃ (13.3 g, 95.8 mmol)was added. The reaction mixture was stirred at room temperatureovernight. Methyl t-butyl ether (300 mL) and water (200 mL) were addedto the mixture, and the resulting layers were separated. The organiclayer was washed with brine, and concentrated to 60 mL whereuponpetroleum ether (200 mL) was added and stirred. The resultingprecipitate was filtered and rinsed with petroleum ether to provide 18.4g(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one(Efavirenz, 1) as an off-white solid.

Example 14 Preparation of(S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (8)

A suspension of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirredat 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers wereseparated. The organic layer was washed with water (20 mL) andevaporated to dryness to give(S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (8).

¹H NMR (CDCl₃) δ 7.54 (s, 1H), 7.12 (dd, J=8.5, 1.5 Hz, 1H), 6.62 (d,J=8.6 Hz, 1H), 4.47 (br. s, 3H), 1.44-1.35 (m, 1H), 0.93-0.88 (m, 2H),0.83-0.80 (m, 2H).

Example 15 Preparation of(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one(Efavirenz, 1)

A solution of(S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline(4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) wasstirred at room temperature for 10 minutes. The reaction was quenchedwith ice-water (10 mL). The two layers were separated, ethyl acetate (10mL) was added to the toluene layer and the mixture was washed with brine(2×30 mL) and the two layers were separated. The organic layer wasevaporated to dryness to give an orange oil and further crystallizedwith hexanes to give(S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-oneas a white or off-white solid. ¹H NMR (CDCl₃) δ 9.64 (s, 1H), 7.49 (a,s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36(m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H).

Example 16 Preparation ofN,N-bis((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl)-4-chloro-2-(2,2,2-trifluoroacetyl)aniline(11)

A solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 40g, 0.179 mol), (−)-camphanoyl chloride (116 g, 0.537 mol), toluene (120mL), and dichloromethane (100 mL) was stirred at room temperature.Triethylamine (125 mL, 0.895 mol, 5 eq) was added dropwise. The reactionmixture was stirred at room temperature for 1 day. The resultingsuspension was treated with 1N HCl and washed with water and brine. Theorganic layer was separated and evaporated to dryness to provideN,N-bis((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl)-4-chloro-2-(2,2,2-trifluoroacetyl)aniline(11).

Example 17 Preparation of(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10)

2.5M n-Butyllithium (2.05 mL, 5.14 mmol) was added slowly to a solutionof cyclopropyl acetylene (0.34 g, 5.14 mmol) in tetrahydrofuran (4 mL)in an ice-salt-bath under argon, and thenN,N-bis((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl)-4-chloro-2-(2,2,2-trifluoroacetyl)aniline(11, 1 g, 1.71 mmol) in THF (2 mL) was added. The reaction mixture wasstirred for 1 hour. The reaction was quenched with 10% citric acidaqueous, the mixture was extracted with ethyl acetate and the two layerswere separated. The organic layer was evaporated to dryness to give acrude oil and further crystallized with ethyl acetate and petroleumether to give pure(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(10).

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present invention. Any prioritydocument(s) are incorporated herein by reference as if each individualpriority document were specifically and individually indicated to beincorporated by reference herein and as though fully set forth herein.The invention includes all embodiments and variations substantially ashereinbefore described and with reference to the examples and drawings.

1. A compound of Formula 3:

wherein R² is a chiral auxiliary group.
 2. The compound of claim 1wherein the chiral auxiliary group is Q of a chiral acid QCOOH, whereinQCOOH is selected from the group consisting of: natural chiral organicacids, unnatural chiral organic acids, natural amino acid, and unnaturalamino acid.
 3. The compound of claim 1 wherein the chiral auxiliarygroup is a chiral C₄-C₁₀ alkoxyl or a chiral C₆-C₁₂ aralkoxyl group. 4.The compound of claim 1 wherein the chiral auxiliary group is Q of achiral acid QCOOH, wherein QCOOH is selected from the group consistingof: camphanic acid, 2-pyrrolidone-5-carboxylic acid, naproxen,ibuprofen; tartaric acid, malic acid, lactic acid, 3-hydroxybutyricacid, and mandelic acid.
 5. The compound of claim 1 wherein R² is


6. The compound of claim 1 wherein R² is

wherein R⁴ is a hydroxyl protecting group and the carbon centredesignated “*” is enantiomerically enriched in a (R)- or(S)-configuration.
 7. The compound of claim 1 wherein R² is